JP2013532691A - Ligands for selective asymmetric hydroformylation - Google Patents

Abstract

In one aspect, the invention provides a compound of Formula 4, wherein the component variables are defined in the specification. In one aspect, the invention provides compounds of Formulas 1, 2a, 2b, 3a, and 3b. In one aspect, the present invention provides the synthesis of the ligand of formula 4 shown below. In one aspect, the present invention provides the synthesis of 2-phenylpropanal from styrene and synthesis gas in the presence of an Rh catalyst obtained from a ligand of formula 4. In one aspect, the present invention provides the synthesis of 3-methyl-4-oxobutanenitrile from allyl cyanide and synthesis gas in the presence of an Rh catalyst obtained from a ligand of formula 4.

Description

Introduction The present invention relates to phosphine-phosphite ligands having a chiral phospholane (S, S) -diphenylphosphorane and a chiral or achiral biarylphenol linked by a hydroxymethyl bridge. In one aspect, the invention provides a compound of formula 4:

を提供し、式中、構成要素変数は以下に定義される。

Where the component variables are defined below.

Olefin hydroformylation has been practiced industrially for decades to produce primary aldehyde intermediates. Since linear regioisomers are often desired, a major industrial concern is the development of highly linear-selective ligands for rhodium-catalyzed hydroformylation. Several phosphorus-based ligands have been developed that show sufficiently high regioselectivity for linear aldehydes, while this method is industrially applicable. In the general chemical sector, linear regioisomers are almost always desired. However, there is a need for both linear and branched aldehyde regioisomers in the organic synthesis of more complex molecules used in the fine chemical and pharmaceutical sectors. In the latter case, branched regioisomers of aldehydes are also frequently preferred in optically active forms and thus such products can be prepared by regioselective and enantioselective hydroformylation of olefins. Current state-of-the-art catalysts for enantioselective hydroformylation only provide branched aldehyde regioisomers for a selected number of carefully selected olefin substrates. In the case of terminal olefins, these are R—CH═CH ₂ (wherein Ar = aryl, heteroaryl, or heteroatom), and XCH ₂ CH═CH _{2 where} X = heteroatom or CN. Takes form. These catalysts are for hydroformylation of alkenes of the RCH ₂ CH═CH ₂ form, where R refers to an aryl, heteroaryl, or alkyl group, or a functional derivative as defined herein. Supports branched aldehydes, resulting in very poor regioselectivity. Furthermore, there is still an unmet need for state-of-the-art catalysts to achieve very high regioselectivity (> 99%) in the case of olefins that provide only moderate regioselectivity for branched isomers. To do. The invention described herein addresses these unmet needs.

  Significant advances in chiral ligand design have recently been created that have increased enantioselectivity in hydroformylation. Three such advances are described in Ph-BPE [Klosin et al., Angew. Chem. Int. Ed. 2005, 44, 5834], Kelliphite [Whiteker et al., J. Biol. Org. Chem. 2004, 6, 3277], and Binaphos [Takaya et al., J. Biol. Am. Chem. Soc. 1997, 119, 4413]. The structure of these three ligands is shown below in FIG.

Ｐｈ−ＢＰＥは、選択されたオレフィンの非対称ヒドロホルミル化について高い活性およびエナンチオ選択性を示した。ビスホスファイト配位子であるＫｅｌｌｉｐｈｉｔｅは、このクラスの新規配位子の包括的なスクリーニングの後、エナンチオ選択的ヒドロホルミル化に有効であることが発見された。アトロプ異性ビアリール系ホスフィン−ホスファイトであるＢｉｎａｐｈｏｓは、アリール、ヘテロアリール、アルケニル、ヘテロ原子の置換基をもつ様々な末端オレフィン、および様々な内部オレフィンで観察された高いエナンチオ選択性（ｅｎａｎｔｉｏｓｅｌｅｃｔｉｖｉｅｓ）とともに、これまで実証されたおそらく最も広い適用性を伴った、エナンチオ選択的ヒドロホルミル化のための顕著な配位子であることが証明された。高エナンチオ選択性は、これらの反応における共通のフィーチャであり、オレフィン基質は、所望の分岐状異性体を優先的に形成するその傾向について選ばれ、７５％と非常に優れた場合における９９％との間の位置選択性を与える。しかし、他の型のヒドロホルミル化触媒と共通して、ＲＣＨ_２ＣＨ＝ＣＨ_２型のオレフィンのヒドロホルミル化は、選択的に分岐状アルデヒドをもたらさないことも実証されている。「Ａｓｙｍｍｅｔｒｉｃ ｈｙｄｒｏｆｏｒｍｙｌａｔｉｏｎ ｃａｔａｌｙｚｅｄ ｂｙ ａｎ Ｒｈ（Ｉ）−（Ｒ，Ｓ）−ＢＩＮＡＰＨＯＳ ｃｏｍｐｌｅｘ： ｓｕｂｓｔｉｔｕｅｎｔ ｅｆｆｅｃｔｓ ｏｎ ｔｈｅ ｒｅｇｉｏｓｅｌｅｃｔｉｖｉｔｙ」、Ｊ． Ｏｒｇａｎｏｍｅｔ． Ｃｈｅｍ． １９９７年、５２７巻、１０３頁で実証されたように、実際には一般的な基質であるヘキサ−１−エンから形成されるアルデヒドの約２５％のみが所望の分岐状位置異性体である。「Ｓｕｂｓｔｉｔｕｅｎｔ Ｅｆｆｅｃｔ ｉｎ Ａｓｙｍｍｅｔｒｉｃ Ｈｙｄｒｏｆｏｒｍｙｌａｔｉｏｎ ｏｆ Ｏｌｅｆｉｎｓ Ｃａｔａｌｙｓｅｄ ｂｙ Ｒｈｏｄｉｕｍ（Ｉ） Ｃｏｍｐｌｅｘｅｓ ｏｆ （Ｒ，Ｓ）−ＢＩＮＡＰＨＯＳ Ｄｅｒｉｖａｔｉｖｅｓ： Ａ ｐｒｏｔｏｃｏｌ ｆｏｒ ｉｍｐｒｏｖｅｍｅｎｔ ｏｆ ｒｅｇｉｏ− ａｎｄ ｅｎａｎｔｉｏ−ｓｅｌｅｃｔｉｖｉｔｉｅｓ」、Ａｄｖ． Ｓｙｎｔｈ． Ｃａｔａｌ． ２００１年、３４３巻、６１頁に記載された研究は、この状況を改善しようとするものであるが、ヘキサ−１−エンのエナンチオ選択的ヒドロホルミル化について、芳しくない２９．８％の選択性しかもたらさない。したがって、これまでホスフィン−ホスファイトから得られたＲｈ触媒は、トリフェニルホスフィンまたは１，２−ビス−（ジフェニルホスフィノ）エタンなどの単純なアキラルな配位子と、オレフィンのヒドロホルミル化において同様の位置選択性を与えることが広く公知である。この変換のために多くの触媒が調査されてきたにもかかわらず、この問題は未解決のままであり、２つの権威のある総説からの引用文、すなわち、「Ｒｅｃｅｎｔ Ａｄｖａｎｃｅｓ ｉｎ Ｃｈｅｍｏ−，Ｒｅｇｉｏ− ａｎｄ Ｓｔｅｒｅｏｓｅｌｅｃｔｉｖｅ Ｈｙｄｒｏｆｏｒｍｙｌａｔｉｏｎ」、Ｓｙｎｔｈｅｓｉｓ、２００１年、１巻から引用された「特に、単純なアルキル置換アルケンについて、分岐状アルデヒドの好適な形成は、未解決問題である」、および「Ｂｒａｎｃｈｅｄ Ｓｅｌｅｃｔｉｖｅ Ｈｙｄｒｏｆｏｒｍｙｌａｔｉｏｎ」、Ｃｕｒｒ． Ｏｒｇ． Ｃｈｅｍ． ２００５年、９巻、７０１頁における同様の結論に反映されている。「Ｈｙｄｒｏｇｅｎａｔｉｏｎ Ｐｒｏｃｅｓｓｅｓ ｉｎ ｔｈｅ Ｓｙｎｔｈｅｓｉｓ ｏｆ Ｐｅｒｆｕｍｅｒｙ Ｉｎｇｒｅｄｉｅｎｔｓ」、Ａｃｃ． Ｃｈｅｍ． Ｒｅｓ． ２００７年、４０巻、１３１２頁、および「Ｔｈｅ Ｓｙｎｔｈｅｓｉｓ ｏｆ ｔｈｅ Ｈｉｇｈ Ｐｏｔｅｎｃｙ Ｓｗｅｅｔｅｎｅｒ ＮＣ−００６３７ Ｐａｒｔ １： Ｔｈｅ Ｓｙｎｔｈｅｓｉｓ ｏｆ （Ｓ）−２−Ｍｅｔｈｙｌ Ｈｅｘａｎｏｉｃ Ａｃｉｄ」、Ｏｒｇ． Ｐｒｏｃ． Ｒｅｓ． Ｄｅｖ． ２００３年、７巻、３６９頁によって記載されたそれほど直接的でないプロトコールによって立証されているように、このような分岐状アルデヒドまたはこれらから直接得られる生成物について、強い工業上の需要がある。

Ph-BPE showed high activity and enantioselectivity for asymmetric hydroformylation of selected olefins. The bisphosphite ligand Kelliphite was found to be effective for enantioselective hydroformylation after comprehensive screening of this class of novel ligands. Binaphos, an atropisomeric biaryl-based phosphine-phosphite, with a variety of terminal olefins with aryl, heteroaryl, alkenyl, heteroatom substituents, and high enantioselectivities observed with various internal olefins, It has proven to be a prominent ligand for enantioselective hydroformylation, possibly with the broadest applicability demonstrated so far. High enantioselectivity is a common feature in these reactions, and the olefinic substrate is chosen for its tendency to preferentially form the desired branched isomer, with 75% and 99% when very good. Gives position selectivity between. However, in common with other types of hydroformylation catalysts, it has also been demonstrated that hydroformylation of olefins of the RCH ₂ CH═CH ₂ type does not selectively lead to branched aldehydes. “Asymmetrical hydrolyzed catalyzed by an Rh (I)-(R, S) -BINAPHOS complex: substituent effects on the regioselectivity”, J. Am. Organomet. Chem. As demonstrated in 1997, 527, 103, in fact only about 25% of the aldehydes formed from hexa-1-ene, a common substrate, are the desired branched regioisomers. “Substituting Effect in Asymmetry Hydrology of Olefins Catalyzed by Rhodium (I) Complexes of (R, S)-BINAPHOS Derivatives: A Protocol. Synth. Catal. The work described in 2001, 343, 61 attempts to ameliorate this situation, but only a poor 29.8% selectivity for the enantioselective hydroformylation of hexa-1-ene. Will not bring. Thus, Rh catalysts obtained so far from phosphine-phosphites are similar to simple achiral ligands such as triphenylphosphine or 1,2-bis- (diphenylphosphino) ethane, in hydroformylation of olefins. It is widely known to provide position selectivity. Despite many catalysts being investigated for this transformation, the problem remains unresolved and is quoted from two authoritative reviews: “Recent Advances in Chemo—, Regio— and Stereoselective Hydroformation ", Synthesis, 2001, Volume 1," Especially for simple alkyl-substituted alkenes, the preferred formation of branched aldehydes is an open problem ", and" Branched Selective Hydroformation ", Curr. . Org. Chem. This is reflected in a similar conclusion in 2005, volume 9, page 701. “Hydrogenation Processes in the Synthesis of Performance Ingredients”, Acc. Chem. Res. 2007, 40, 1312, and “The Synthesis of the High Potency Sweetener NC-00637 Part 1: The Synthesis of (S) -2-Methyl Hexanoic Acid”, Org. Proc. Res. Dev. There is a strong industrial demand for such branched aldehydes or products obtained directly from them, as evidenced by the less direct protocol described by 2003, Volume 7, 369.

  Phosphine-phosphites have been reported to lack a diphenylphosphorane moiety. The closest example is from Landis using a 1,2-benzene backbone and a diazaphosphorane moiety for phosphine, and the best results for these ligands are “Highly Enantiomers of Hybrid Alkenes with Diazophosphoranes” , Organic Letters, 2008, 10 (20), page 4553, 90% e.e. with b / l = 20 for styrene. e. It is. As a further example of a phosphine-phosphite that does not contain a phospholane moiety, see “Asymmetric Hydroformation USING Taddol-Based Chiral Phosphine-Phosophylide Ligands”, Organficlics 2010, 29 f. “Modified with Chiral Phosphine-Phosphyte Ligands”, Organometallics 2007, 26 (25), 6428; “Synthesis of a chiral phosphine-phosphine” ligand, its coordination behavior with rhodium (I) cation and the application in catalytic reaction ", Zhongshan Daxue Xuebao, Ziran Kexueban, 2006 years, Vol. 45 (No. 4), page 58;" Tuning of the structures of chiral phosphane-phosphites: application to the highly enantioselective synthesis of α-acrylic phosphonates by catalytic hydrogenation, Chemistry-A European Juou. nal 2007 years, Vol. 13 (No. 6), and a 1821 pages.

“Rhodium (I), Palladium (II), and Platinum (II)” Complexes Containing New Mixed Phase-Phosphoretic Eligent Effects of the United States of America. J. et al. Inorg. Chem. The work described in 711, 2002, page 711 contains a CH ₂ O backbone, but chiral phosphine-phosphites lacking a phospholane moiety are precedent, but any notable enantioselectivity. It also shows not giving.

Despite the widespread nature of phosphine-phosphites, it is clear that there are no examples (as opposed to diazaphosphorane groups) containing a phospholane group as the phosphine moiety of the ligand. Second, since there is no obvious precedent to solve the regioselectivity control problem in hydroformylation of olefins of the RCH ₂ CH═CH ₂ type, a study of this unique ligand class was conducted and the present specification It came to the invention described in. Hydroxymethyl bridge was chosen as the first starting backbone because of its ease of synthesis. This family of ligands therefore uses a diphenylphosphorane moiety as the phosphine donor and CH ₂ O as the backbone. As a result, they are easy to make from previously reported phosphine-phosphites. More importantly, the results obtained using these ligands indicate that they have a unique performance in producing branched aldehydes in hydroformylation of olefins of the RCH ₂ CH═CH ₂ type. In addition, we show that it provides the best combination of regioselectivity and enantioselectivity observed with hydroformylation of other olefin substrates. These ligands provide ease of synthesis, higher enantioselectivity, and higher regioselectivity.

In one aspect, the invention provides a compound of Formula 4:

を提供し、式中、構成要素変数は以下に定義される。

Where the component variables are defined below.

DETAILED DESCRIPTION In one aspect, the present invention provides a compound of formula 4:

（式中、ｎおよびｍは、それぞれ独立に、１〜３の整数であり；
Ａｒ^１はともに、独立して、Ｃ_６〜Ｃ_１４アリールまたはＣ_１〜Ｃ_９ヘテロアリールであり、これらは、非置換であっても、以下の基：Ｃ_１〜Ｃ_６アルキル−、ハロゲン、Ｃ_１〜Ｃ_６ハロアルキル−、ヒドロキシル、ヒドロキシル（Ｃ_１〜Ｃ_６アルキル）−、Ｈ_２Ｎ−、（Ｃ_１〜Ｃ_６アルキル）アミノ−、ジ（Ｃ_１〜Ｃ_６アルキル）アミノ−、ＨＯ_２Ｃ−、（Ｃ_１〜Ｃ_６アルコキシ）カルボニル−、（Ｃ_１〜Ｃ_６アルキル）カルボキシル−、ジ（Ｃ_１〜Ｃ_６アルキル）アミド−、Ｈ_２ＮＣ（Ｏ）−、（Ｃ_１〜Ｃ_６アルキル）アミド−、またはＯ_２Ｎ−のうちの１つまたは複数で置換されていてもよく；
−Ａｒ^２−Ａｒ^２−は、ビ（Ｃ_６〜Ｃ_１４アリール）、ビ（Ｃ_１〜Ｃ_９ヘテロアリール）、または−（Ｃ_６〜Ｃ_１４アリール）−（Ｃ_１〜Ｃ_９ヘテロアリール）−ジラジカルであり、これは、非置換であっても、以下の基、すなわち、Ｃ_１〜Ｃ_６アルキル−、ハロゲン、Ｃ_１〜Ｃ_６ハロアルキル−、ヒドロキシル、ヒドロキシル（Ｃ_１〜Ｃ_６アルキル）−、Ｈ_２Ｎ−、（Ｃ_１〜Ｃ_６アルキル）アミノ−、ジ（Ｃ_１〜Ｃ_６アルキル）アミノ−、ＨＯ_２Ｃ−、（Ｃ_１〜Ｃ_６アルコキシ）カルボニル−、（Ｃ_１〜Ｃ_６アルキル）カルボキシル−、ジ（Ｃ_１〜Ｃ_６アルキル）アミド−、Ｈ_２ＮＣ（Ｏ）−、（Ｃ_１〜Ｃ_６アルキル）アミド−、またはＯ_２Ｎ−のうちの１つまたは複数で置換されていてもよい）。

Wherein n and m are each independently an integer of 1 to 3;
Both Ar ¹ are independently C ₆ -C ₁₄ aryl or C ₁ -C ₉ heteroaryl, which, if unsubstituted, are the following groups: C ₁ -C ₆ alkyl-, halogen, C ₁ -C ₆ haloalkyl -, hydroxyl, hydroxyl _(C 1 -C _{6 alkyl) -, H 2 N -,} (C 1 ~C 6 alkyl) amino -, di _(C 1 -C ₆ alkyl) amino -, HO ₂ C-, (C ₁ -C ₆ alkoxy) carbonyl-, (C ₁ -C ₆ alkyl) carboxyl-, di (C ₁ -C ₆ alkyl) amide-, H ₂ NC (O)-, (C _1- Optionally substituted with one or more of C ₆ alkyl) amido-, or O ₂ N-;
—Ar ² —Ar ² — is bi (C ₆ -C ₁₄ aryl), bi (C ₁ -C ₉ heteroaryl), or — (C ₆ -C ₁₄ aryl)-(C ₁ -C ₉ heteroaryl). A diradical, which, even if unsubstituted, has the following groups: C ₁ -C ₆ alkyl-, halogen, C ₁ -C ₆ haloalkyl-, hydroxyl, hydroxyl (C ₁ -C ₆ alkyl) _{-, H 2 N -, (} C 1 ~C 6 alkyl) amino -, di _(C 1 -C ₆ alkyl) amino _{-, HO 2 C -, (} C 1 ~C 6 alkoxy) carbonyl -, _(C 1 ~ C ₆ alkyl) carboxyl -, di _(C 1 -C ₆ alkyl) amide _{-, H 2 NC (O)} -, (C 1 ~C 6 alkyl) amide - or _O 2 N-1 or more of the May be substituted).

  In one aspect, the present invention provides compound 3b (the crystal structure of FIG. 3 and FIG. 4).

一態様では、本発明は、式１、２ａ、２ｂ、３ａ、および３ｂの化合物を提供する。

In one aspect, the invention provides compounds of Formulas 1, 2a, 2b, 3a, and 3b.

一態様では、本発明は、以下に示す式４の配位子の合成を提供する。

In one aspect, the present invention provides the synthesis of the ligand of formula 4 shown below.

一態様では、本発明は、式４の配位子から得られるＲｈ触媒の存在下での、スチレンおよび合成ガスからの２−フェニルプロパナールの合成を提供する。

In one aspect, the present invention provides the synthesis of 2-phenylpropanal from styrene and synthesis gas in the presence of an Rh catalyst obtained from a ligand of formula 4.

一態様では、本発明は、式４の配位子から得られるＲｈ触媒の存在下での、シアン化アリルおよび合成ガスからの３−メチル−４−オキソブタンニトリルの合成を提供する。

In one aspect, the present invention provides the synthesis of 3-methyl-4-oxobutanenitrile from allyl cyanide and synthesis gas in the presence of an Rh catalyst obtained from a ligand of formula 4.

一態様では、本発明は、式４の配位子から得られるＲｈ触媒の存在下での、酢酸ビニルおよび合成ガスからの１−オキソプロパン−２−イルアセテートの合成を提供する。

In one aspect, the present invention provides the synthesis of 1-oxopropan-2-yl acetate from vinyl acetate and synthesis gas in the presence of an Rh catalyst obtained from a ligand of formula 4.

３ｂのＲｈ錯体のｉｎ−ｓｉｔｕ形成を使用するこれらの結果を表１に要約する。

These results using in-situ formation of the 3b Rh complex are summarized in Table 1.

表１では、型４の配位子から得られる触媒を使用する、スチレンの上記ヒドロホルミル化についての結果が示され、最もエナンチオ選択性の配位子として配位子３ｂが同定された。

Table 1 shows the results for the above hydroformylation of styrene using a catalyst obtained from a type 4 ligand and identified ligand 3b as the most enantioselective ligand.

  Table 1; Rh catalyzed the hydroformylation of styrene.

^ａ Ｔ＝３０℃、Ｓ：Ｃ＝２５０：１、０．４％の［Ｒｈ（ａｃａｃ）（ＣＯ）_２］、および配位子１〜３ｂ（０．５％）、１ｍｍｏｌのスチレン、トルエン３．５ｍＬから形成される触媒
^ｂ βＤｅｘ２２５キラルカラム上の粗反応混合物のＧＣによる計算
^ｃ 初期圧力＝１０バール。

^a T = 30 ° C., S: C = 250: 1, 0.4% [Rh (acac) (CO) ₂ ], and ligands 1-3b (0.5%), 1 mmol styrene, toluene 3 . Catalyst formed from 5 mL
^b GC calculation of crude reaction mixture on βDex225 chiral column
^c Initial pressure = 10 bar.

  In one aspect, the present invention provides a ligand other than the phosphorane-phosphite class in the presence of an Rh catalyst obtained from a type 4 ligand under conditions that do not provide any of the selectivity shown in Table 2. Provides a regioselective synthesis of 2-methyl-3-phenylpropane-1-al from allylbenzene and synthesis gas.

  Table 2. Hydroformylation of allylbenzene using various hydroformylation catalysts at 15 ° C

［ａ］トルエン（３ｍｌ）中、５バールの合成ガスで、５０℃で４０分間撹拌することによって、０．４％の［Ｒｈ（ａｃａｃ）（ＣＯ）_２］および０．５％の二座配位子または１．２％の単座配位子から触媒を予め形成した後、５バールの初期合成ガス圧で、室温で３日間反応を実行した。Ｄｐｐｅ＝１，２−ビス−（ジフェニルホスフィノ）エタン
［ｂ］内部標準としてテトラエチルシランを使用して^１Ｈ ＮＭＲによって決定した％生成物
［ｃ］ＮａＢＨ_４（Ｃｈｉｒａｃｅｌ ＯＤ−Ｈ）で還元した後に形成されたアルコールのＨＰＬＣ分析によって決定した
［ｄ］２ステップにわたる、対応するアルコールの５３％の単離収率
［ｅ］３０℃で４時間の反応時間。

[A] 0.4% [Rh (acac) (CO) ₂ ] and 0.5% bidentate by stirring for 40 minutes at 50 ° C. with 5 bar synthesis gas in toluene (3 ml) After preforming the catalyst from ligands or 1.2% monodentate ligand, the reaction was carried out at room temperature for 3 days at an initial synthesis gas pressure of 5 bar. Dppe = 1,2-bis- (diphenylphosphino) ethane [b] after reduction with% product [c] NaBH ₄ (Chiracel OD-H) determined by ¹ H NMR using tetraethylsilane as internal standard [D] 53% isolated yield of the corresponding alcohol over two steps [e] determined by HPLC analysis of the alcohol formed [e] 4 h reaction time at 30 ° C.

In one aspect, the present invention provides that the natural regioselectivity of Rh-catalyzed hydroformylation from olefins of the RCH ₂ CH═CH ₂ type as defined above to linear aldehydes is a catalytic ligand. By using phosphorane-phosphite as a method is provided that is reversed to the branched regioisomer.

Definitions Unless otherwise suggested by context, the following definitions are used in connection with the present invention. BH ₃ DMS is borane dimethyl sulfide complex ((CH ₃ ) ₂ SBH ₃ ), DABCO is 1,4-diazabicyclo [2.2.2] octane, r. t. Is room temperature and TMS-I is iodotrimethylsilane. The term “% ee” means the enantiomeric excess of a substance, which is defined as the absolute difference between the molar fractions of each enantiomer.

In general, the number of carbon atoms present in a given group is designated as “C _x -C _y ”, where x and y are lower and upper limits, respectively. For example, a group designated as “C ₁ -C ₆ ” contains 1 to 6 carbon atoms. Carbon number, as defined herein, refers to main chain and branched carbons, but does not include carbon atoms of substituents such as alkoxy substituents. Unless specified otherwise, nomenclature of substituents not specifically defined herein is accomplished by naming the terminal functionality of the functionality, adjacent functionality toward its subsequent point of attachment, from left to right. It is done. For example, the substituent “arylalkyloxycarbonyl” refers to the group (C ₆ -C ₁₄ aryl)-(C ₁ -C ₆ alkyl) -O—C (O) —. It is understood that the above definitions are not intended to include unacceptable substitution patterns (eg, methyl substituted with 5 fluoro groups). Such unacceptable substitution patterns are well known to those skilled in the art. Carbon number, as defined herein, refers to main chain carbon and carbon branched carbon, but does not include carbon atoms of substituents such as alkoxy substituents.

“(Alkoxy) carbonyl” refers to the group alkyl-O—C (O) —. Exemplary (C ₁ -C ₆ alkoxy) carbonyl groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy, and t-butoxy. The (alkoxy) carbonyl group may be unsubstituted or substituted with one or more of the following groups: halogen, hydroxyl, —NH ₂ , (C ₁ -C ₆ alkyl) N— , _(C 1 ~C _{6 alkyl) (C} 1 _{~C 6 alkyl) N -, - N (C} 1 ~C 3 _{alkyl) C (O) (C 1} ~C 6 alkyl), - NHC (O) ( C ₁ -C _{6 alkyl), - NHC (O) H} , -C (O) NH 2, -C (O) NH (C 1 ~C 6 _{alkyl), - C (O) N} (C 1 ~C 6 alkyl ) _(C 1 ~C _{6 alkyl), - CN, C 1 ~C} 6 alkoxy, -C (O) OH, -C (O) O (C 1 ~C 6 alkyl), - C (O) ( C 1 -C _{6 alkyl), C} 6 ~C _{14 aryl,} C 1 -C _{9 heteroaryl,} C 3 -C ₈ cycloalkyl alkyl, C ₁ -C ₆ haloalkyl _-, C 1 -C ₆ aminoalkyl _{-, - OC (O) (} C 1 ~C 6 _alkyl), C 1 -C ₆ carboxamido alkyl -, or _-NO 2.

“Alkyl-” refers to a straight or branched hydrocarbon chain containing the indicated number of carbon atoms, for example, a C ₁ -C ₁₀ alkyl-group in which 1 to 10 (inclusive) carbon atoms. In the absence of any numerical designation, “alkyl” is a chain (straight or branched) having 1 to 6 (inclusive) carbon atoms in it. Examples of C ₁ -C ₆ alkyl-groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. . Alkyl-groups can be unsubstituted or substituted with one or more of the following groups: halogen, H ₂ N—, (C ₁ -C ₆ alkyl) amino-, di ( C ₁ -C ₆ alkyl) amino-, (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₃ alkyl)-, (C ₁ -C ₆ alkyl) carboxamide-, HC (O) NH _{-, H 2 NC (O)} -, (C 1 ~C 6 alkyl) NHC (O) -, di _(C 1 -C ₆ alkyl) NC (O) -, NC- , _hydroxyl, C 1 -C ₆ alkoxy _-, C 1 ~C ₆ alkyl _{-, HO 2 C -, (} C 1 ~C 6 alkoxy) carbonyl _{-, (C} 1 ~C _{6 alkyl) C (O) -, C} 6 ~C 14 aryl -, _{C 1} -C ₉ heteroaryl _-, C 3 ~C ₈ cycloalkyl _-, C 1 ~C ₆ halo Alkyl -, amino _(C 1 -C ₆ alkyl) _{-, (C} 1 -C ₆ alkyl) carboxyl _-, C 1 -C ₆ carboxamido alkyl -, or _O 2 N-.

“(Alkyl) amido-” refers to the group —C (O) NH—, wherein the nitrogen atom of the group is bound to an alkyl group as defined above. Representative examples of (C ₁ -C ₆ alkyl) amide groups include, but are not limited to, —C (O) NHCH ₃ , —C (O) NHCH ₂ CH ₃ , —C (O) NHCH ₂ CH ₂ CH ₃ , —C (O) NHCH ₂ CH ₂ CH ₂ CH ₃ , —C (O) NHCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ , —C (O) NHCH (CH ₃ ) ₂ , —C (O) NHCH ₂ CH (CH ₃ ) ₂ , —C (O) NHCH (CH ₃ ) CH ₂ CH ₃ , —C (O) NH—C (CH ₃ ) ₃ and —C (O) NHCH ₂ C (CH ₃ ) ₃ Is mentioned.

“(Alkyl) amino-” refers to the group —NH, wherein the nitrogen atom of the group is bound to an alkyl group as defined above. Representative examples of (C ₁ -C ₆ alkyl) amino-groups include, but are not limited to, CH ₃ NH—, CH ₃ CH ₂ NH—, CH ₃ CH ₂ CH ₂ NH—, CH ₃ CH ₂ CH _{2. CH 2 NH -, (CH 3} ) 2 CHNH -, (CH 3) 2 CHCH 2 NH-, CH 3 CH 2 CH (CH 3) NH-, and _{(CH 3) 3} CNH- and the like. (Alkyl) amino groups may be unsubstituted or substituted with one or more of the following groups: halogen, H ₂ N—, (C ₁ -C ₆ alkyl) amino-, Di (C ₁ -C ₆ alkyl) amino-, (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₃ alkyl)-, (C ₁ -C ₆ alkyl) carboxamide-, HC (O _{) NH-, H 2 NC (O} ) -, (C 1 ~C 6 alkyl) NHC (O) -, di _(C 1 -C ₆ alkyl) NC (O) -, NC- , _hydroxyl, C 1 -C ₆ alkoxy _-, C 1 -C ₆ alkyl _{-, HO 2 C -, (} C 1 ~C 6 alkoxy) carbonyl _{-, (C} 1 -C _{6 alkyl) C (O) -, C} 6 ~C 14 aryl -, C ₁ -C ₉ heteroaryl _-, C 3 ~C ₈ cycloalkyl _{-, C} 1 ~ ₆ haloalkyl -, amino _(C 1 -C ₆ alkyl) _{-, (C} 1 -C ₆ alkyl) carboxyl _-, C 1 -C ₆ carboxamido alkyl -, or _O 2 N-.

“Alkylcarboxy” refers to an alkyl group, as defined above, attached to the parent structure through a carboxyl (C (O) —O—) functional oxygen atom. Examples of (C ₁ -C ₆ alkyl) carboxy include acetoxy, ethylcarboxy, propylcarboxy, and isopentylcarboxy.

“Aryl-” refers to an aromatic hydrocarbon group. Examples of C ₆ -C ₁₄ aryl-groups include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, 3-biphen-1-yl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. included. An aryl group can be unsubstituted or substituted with one or more of the following groups: C ₁ -C ₆ alkyl-, halogen, haloalkyl-, hydroxyl, hydroxyl (C ₁ -C ₆ alkyl) _-, H 2 N-, amino _(C 1 -C ₆ alkyl) -, di _(C 1 -C ₆ alkyl) amino _{-, HO 2 C -, (} C 1 ~C 6 alkoxy) carbonyl -, ( C ₁ -C ₆ alkyl) carboxyl -, di _(C 1 -C ₆ alkyl) amide _{-, H 2 NC (O)} -, (C 1 ~C 6 alkyl) amide - or _O 2 N-.

“Di (alkyl) amido-” refers to the group —NC (O) —, wherein the nitrogen atom of the group is bonded to two alkyl groups as defined above. Each alkyl group can be independently selected. Representative examples of di (C ₁ -C ₆ alkyl) amido-groups include, but are not limited to, —C (O) N (CH ₃ ) ₂ , —C (O) N (CH ₂ CH ₃ ) ₂ , _{-C (O) N (CH 3} ) CH 2 CH 3, -C (O) N (CH 2 CH 2 CH 2 CH 3) 2, -C (O) N (CH 2 CH 3) CH 2 CH 2 CH ₃ , —C (O) N (CH ₃ ) CH (CH ₃ ) ₂ , —C (O) N (CH ₂ CH ₃ ) CH ₂ CH (CH ₃ ) ₂ , —C (O) N (CH (CH _{3) CH 2 CH 3) 2} , include _{-C (O) N (CH 2} CH 3) C (CH 3) 3 and _{-C (O) N (CH 2} CH 3) CH 2 C (CH 3) 3 It is done.

“Di (alkyl) amino-” refers to a nitrogen atom bonded to two alkyl groups as defined above. Each alkyl group can be independently selected. Di _(C 1 -C ₆ alkyl) amino - Representative examples of groups include, but are not limited _{to, -N (CH 3) 2,} -N (CH 2 CH 3) (CH 3), - N (CH 2 _{CH 3) 2, -N (CH} 2 CH 2 CH 3) 2, -N (CH 2 CH 2 CH 2 CH 3) 2, -N (CH (CH 3) 2) 2, -N (CH (CH 3 ) ₂ ) (CH ₃ ), —N (CH ₂ CH (CH ₃ ) ₂ ) ₂ , —NH (CH (CH ₃ ) CH ₂ CH ₃ ) ₂ , —N (C (CH ₃ ) ₃ ) _{2, N (C (CH 3) 3} ) (CH 3), and _{-N (CH 3) (CH 2} CH 3) and the like. Two alkyl groups on the nitrogen atom, when taken together with the nitrogen to which they are attached, can form a 3-7 membered nitrogen-containing heterocycle, where the carbon atom of the heterocycle up to 2 carbon atoms of, -N (H) -, - N (C 1 ~C 6 _{alkyl) -, - N (C 3} ~C 8 _{cycloalkyl) -, - N (C 6} ~C _{14 aryl) -, - N (C 1} ~C 9 heteroaryl) -, - N (amino _(C 1 -C _{6 alkyl)) -, - N (C} 6 ~C 14 aryl amino) -, - O-, It can be replaced with -S-, -S (O)-, or -S (O) _2- .

  “Halo” or “halogen” refers to fluorine, chlorine, bromine, or iodine.

“Haloalkyl-” refers to an alkyl group as defined above, wherein one or more of the hydrogen atoms of the C ₁ -C ₆ alkyl group is replaced with —F, —Cl, —Br, or —I. Point to. Each substitution can be independently selected from -F, -Cl, -Br, or -I. Representative examples of C ₁ -C ₆ haloalkyl-groups include, but are not limited to, —CH ₂ F, —CCl ₃ , —CF ₃ , CH ₂ CF ₃ , —CH ₂ Cl, —CH ₂ CH ₂ Br, _{-CH 2 CH 2 I, -CH 2} CH 2 CH 2 F, -CH 2 CH 2 CH 2 Cl, -CH 2 CH 2 CH 2 CH 2 Br, -CH 2 CH 2 CH 2 CH 2 I, -CH 2 _{CH 2 CH 2 CH 2 CH 2} Br, -CH 2 CH 2 CH 2 CH 2 CH 2 I, -CH 2 CH (Br) CH 3, -CH 2 CH (Cl) CH 2 CH 3, -CH (F) CH ₂ CH ₃ and _{-C (CH 3) 2 (CH} 2 Cl) and the like.

“Heteroaryl-” refers to 5-10 membered monocyclic and bicyclic aromatic groups containing at least one heteroatom selected from oxygen, sulfur, and nitrogen. Examples of monocyclic C ₁ -C ₉ heteroaryl- groups include, but are not limited to, oxazinyl, thiazinyl, diazinyl, triazinyl, thiadiazoyl, tetrazinyl, imidazolyl, tetrazolyl, isoxazolyl, furanyl, furazanyl, oxazolyl, thiazolyl, And thiophenyl, pyrazolyl, triazolyl, pyrimidinyl, N-pyridyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl. Examples of bicyclic C ₁ -C ₉ heteroaryl- groups include, but are not limited to, benzimidazolyl, indolyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indazolyl, quinolinyl, quinazolinyl, purinyl, benzoisoxazolyl, benzoxazolyl Benzothiazolyl, benzodiazolyl, benzotriazolyl, isoindolyl, and indazolyl. Contemplated heteroaryl-rings or ring systems have a minimum of 5 members. Thus, for example, a C ₁ heteroaryl-group should include, but is not limited to, tetrazolyl, and a C ₂ heteroaryl-group includes, but is not limited to, triazolyl, thiadiazoyl, and tetrazinyl; C ₉ heteroaryl-groups include, but are not limited to, quinolinyl and isoquinolinyl. A heteroaryl group can be unsubstituted or substituted with one or more of the following groups: C ₁ -C ₆ alkyl-, halogen, C ₁ -C ₆ haloalkyl-, hydroxyl, C ₁ -C ₆ hydroxylalkyl-, H ₂ N—, amino (C ₁ -C ₆ alkyl), di (C ₁ -C ₆ alkyl) amino-, —COOH, (C ₁ -C ₆ alkoxy) carbonyl-, _(C 1 -C ₆ alkyl) carboxyl -, di _(C 1 -C ₆ alkyl) amide _{-, H 2 NC (O)} -, (C 1 ~C 6 alkyl) amide - or _O 2 N-.

“Hydroxylalkyl-” refers to an alkyl group as defined above, wherein one or more of the hydrogen atoms of the C ₁ -C ₆ alkyl group has been replaced with a hydroxyl group. Examples of hydroxyl (C ₁ -C ₆ alkyl)-moieties include, for example, —CH ₂ OH, —CH ₂ CH ₂ OH, —CH ₂ CH ₂ CH ₂ OH, —CH ₂ CH (OH) CH ₂ OH, _{-CH 2 CH (OH) CH 3} , include _{-CH (CH 3) CH 2 OH} , and higher homologues.

“Leaving group” refers to an atom or group that is separated (charged or uncharged) from atoms that are considered to be the remaining or major portion of the substrate in a specified reaction. For example, in the anisotropic solvolysis of benzyl bromide in acetic acid, the leaving group is bromide. In the reaction of N, N, N-trimethyl-1-phenylmethanaminium ion with methanethiolate, the leaving group is trimethylamine. For electrophilic nitration of benzene, this is H ⁺ . This term has meaning only in relation to the specified reaction. Examples of leaving groups include, for example, carboxylate (ie, CH ₃ COO ⁻ , CF ₃ CO ₂ ⁻ , or (CH ₃ ) ₂ CH ₂ COO ⁻ ), F ⁻ , water, Cl ⁻ , Br ⁻ , I ^−. , N ₃ ⁻ , SCN ⁻ , trichloroacetimidate, thiopyridyl, tertiary amine (ie trimethylamine), phenoxide (ie o-nitrophenoxide), and sulfonate (ie tosylate, mesylate or triflate). .

  Certain specific aspects and embodiments of the present application are described in more detail with reference to the following examples. These are provided for illustrative purposes only and should not be construed as limiting the scope of the application in any way. Reasonable variations of the procedures described are intended to be within the scope of the present invention. While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. Accordingly, it is intended to embrace all such changes and modifications as fall within the scope of the appended claims.

Diphenyl phosphorane -CH ₂ O part:

ビスホスファイト部分：

Bisphosphite moiety:

配位子形成：

Ligand formation:

（実施例１）
配位子（３ｂ）の調製
ステップ１：

Example 1
Preparation of ligand (3b) Step 1:

（Ｓ）−３，３’−ジ−ｔｅｒｔ−ブチル−５，５’，６，６’−テトラメチル−［１，１’−ビフェニル］−２，２’−ジオール］（（Ｓ）−ＢＩＰＨＥＮ）（２．００ｇ、５．６４ｍｍｏｌ）およびトリエチルアミン（１．６５ｍＬ、１．２０ｇ、１１．８４ｍｍｏｌ、２．１当量）を含有するシュレンクフラスコに、三塩化リン（５１７μＬ、８１４ｍｇ、５．９２ｍｍｏｌ、１．０５当量）を添加し、反応物を室温で一晩撹拌した。次いで、粗反応混合物を窒素雰囲気下で濾過し、トルエン（３×５ｍＬ部分）を残渣に添加し、減圧下で除去することによって、いずれの残留三塩化リンも除去して無色固体を残した。粗製の^３１Ｐ ＮＭＲ（１２１．４ＭＨｚ、Ｃ_６Ｄ_６）スペクトルは、δ_Ｐ＝１７８．８ｐｐｍで１本のピークを示し、（Ｓ）−ＢＩＰＨＥＮクロロホスファイトに対応した。窒素雰囲気下のグローブボックス内で、上記からの（Ｓ）−ＢＩＰＨＥＮクロロホスファイト（１．０ｇ、２．３９ｍｍｏｌ）をトルエン中に溶解させ、過剰のヨウ化トリメチルシリル（１．５ｍＬ、２．１１ｇ、１０．５３ｍｍｏｌ）を添加し、反応混合物を室温で２時間撹拌したままにした。次いで、過剰のヨウ化トリメチルシリルを減圧下で除去し、トルエン（３×５ｍＬ部分）を残渣に添加し、減圧下で除去することによって、いずれの残留ヨウ化トリメチルシリルも除去した。粗製の^３１Ｐ ＮＭＲ（１２１．４ＭＨｚ、Ｃ_６Ｄ_６）スペクトルは、２本のピーク、すなわち、δ_Ｐ＝１７８．８ｐｐｍにおける１本のピーク、およびδ_Ｐ＝２２２．１ｐｐｍにおける別のピークを示し、所望のヨード−ホスファイト（３）への部分的な変換のみを示した。この混合物を、さらに精製することなく以下のカップリングステップにおいて使用して配位子（３ｂ）を形成した。

(S) -3,3′-di-tert-butyl-5,5 ′, 6,6′-tetramethyl- [1,1′-biphenyl] -2,2′-diol] ((S) -BIPHEN ) (2.00 g, 5.64 mmol) and triethylamine (1.65 mL, 1.20 g, 11.84 mmol, 2.1 equiv) in a Schlenk flask (517 μL, 814 mg, 5.92 mmol, 1 .05 equivalents) was added and the reaction was stirred at room temperature overnight. The crude reaction mixture was then filtered under a nitrogen atmosphere and toluene (3 × 5 mL portion) was added to the residue and removed under reduced pressure to remove any residual phosphorus trichloride leaving a colorless solid. The crude ³¹ P NMR (121.4 MHz, C ₆ D ₆ ) spectrum showed one peak at δ _P = 178.8 ppm, corresponding to (S) -BIPHEN chlorophosphite. In a glove box under a nitrogen atmosphere, (S) -BIPHEN chlorophosphite from above (1.0 g, 2.39 mmol) was dissolved in toluene and excess trimethylsilyl iodide (1.5 mL, 2.11 g, 10.53 mmol) was added and the reaction mixture was left stirring at room temperature for 2 hours. Excess trimethylsilyl iodide was then removed under reduced pressure and any residual trimethylsilyl iodide was removed by adding toluene (3 × 5 mL portions) to the residue and removing under reduced pressure. _{^{31 P NMR (121.4MHz, C 6}} D 6) spectrum of the crude, two peaks, namely, shows another peak at one peak, and δ _P = 222.1ppm in [delta] _P = 178.8 ppm Only partial conversion to the desired iodo-phosphite (3) was shown. This mixture was used in the following coupling step without further purification to form the ligand (3b).

  Step 2:

すべての手順、反応は、窒素雰囲気下のグローブボックス内で実施した。トルエン（１０ｍＬ）中の、ホスホラン（７０７ｍｇ、２．３９ｍｍｏｌ、１当量）およびクロロ−ホスファイトとヨード−ホスファイト（２．３９ｍｍｏｌ）との混合物の溶液を含有するシュレンクフラスコに、１，４−ジアザビシクロ−［２，２，２］−オクタン（ＤＡＢＣＯ、１．３４ｇ、１１．９５ｍｍｏｌ、５当量）を添加し、溶液を室温で一晩撹拌したままにした。生成物を、シリカを通して濾過した後、淡黄色油状物として単離し、これは、放置すると淡黄色結晶に固化した。収量：５４７ｍｇ、０．８４ｍｍｏｌ、（３５％）。α_Ｄ ^２５＝＋３８７．１°（ｃ＝０．４１、トルエン）；^３１Ｐ ＮＭＲ （１２１．４ ＭＨｚ，Ｃ_６Ｄ_６） δ_Ｐ＝１３９．３ （Ｐ１），２２．５ （Ｐ４）； ^１Ｈ ＮＭＲ （４００ ＭＨｚ，Ｃ_６Ｄ_６） δ_Ｈ＝７．００−７．３０ （ｍ，１２Ｈ，ＡｒＣＨ），４．０９−４．２１ （ｍ，１Ｈ，Ｃ３Ｈ），３．２４−３．４９ （ｍ，３Ｈ，Ｃ３Ｈ’，Ｃ５ＨおよびＣ８Ｈ），２．１２−２．２６ （ｍ，１Ｈ，Ｃ６ＨまたはＣ７Ｈ），２．０９ （ｓ，３Ｈ，ＣＨ_３），２．０８ （ｓ，３Ｈ，ＣＨ_３），１．８３−１．９５ （ｍ，２Ｈ，Ｃ６Ｈ２またはＣ７Ｈ２），１．７８ （ｓ，３Ｈ，ＣＨ_３），１．６２ （ｓ，３Ｈ，ＣＨ_３），１．５０−１．６０ （ｍ，１Ｈ，Ｃ６ＨまたはＣ７Ｈ），１．５０ （ｓ，９Ｈ，Ｃ（ＣＨ_３）_３），１．３８ （ｓ，９Ｈ，Ｃ（ＣＨ_３）_３）； ^１３Ｃ ＮＭＲ （７５．５ ＭＨｚ，Ｃ_６Ｄ_６） δ_Ｃ＝１４６．７３，１４６．６８，１４６．０５，１４６．０３，１４４．５９，４４．４０，１３８．５２，１３８．５０，１３８．４８，１３８．４５，１３７．３０，１３５．３２，１３４．５９，１３２．６６，１３２．２４，１３２．１９，１３１．６２，１３１．２７，１３１．２４ （ＡｒＣｑｕａｔ．），１２８．７１，１２８．６９，１２８．６２，１２８．３４，１２８．２５，１２８．００，１２７．９６，１２６．１４，１２６．１２，１２６．０４，１２６．０２ （ＡｒＣＨ），６２．４０ （ｄｄ，１ＪＣ−Ｐ＝２９．０，３．７ Ｈｚ，Ｃ３），４６．２０ （ｄ，１ＪＣ−Ｐ＝１５．９ Ｈｚ，Ｃ５またはＣ８），４５．４５ （ｄ，１ＪＣ−Ｐ＝１４．９ Ｈｚ，Ｃ５またはＣ８），３６．４２ （Ｃ６またはＣ７），３２．６７ （ｄ，２ＪＣ−Ｐ＝３．１ Ｈｚ，Ｃ６またはＣ７），３１．７６ （ｄ，Ｊ＝５．０ Ｈｚ，Ｃ（ＣＨ_３）_３），３１．２９ （Ｃ（ＣＨ_３）_３），２０．４ （ＣＨ_３），２０．３７ （ＣＨ_３），１６．７４ （ＣＨ_３），１６．４５ （ＣＨ_３）。

All procedures and reactions were performed in a glove box under a nitrogen atmosphere. A Schlenk flask containing a solution of phosphorane (707 mg, 2.39 mmol, 1 eq) and a mixture of chloro-phosphite and iodo-phosphite (2.39 mmol) in toluene (10 mL) was charged with 1,4-diazabicyclo -[2,2,2] -Octane (DABCO, 1.34 g, 11.95 mmol, 5 eq) was added and the solution was left stirring at room temperature overnight. The product was filtered through silica and then isolated as a pale yellow oil that solidified to pale yellow crystals on standing. Yield: 547 mg, 0.84 mmol, (35%). α _D ²⁵ = + 387.1 ° (c = 0.41, toluene); ³¹ P NMR (121.4 MHz, C ₆ D ₆ ) δ _P = 139.3 (P1), 22.5 (P4); ¹ H NMR (400 MHz, C ₆ D ₆ ) δ _H = 7.00-7.30 (m, 12H, ArCH), 4.09-4.21 (m, 1H, C3H), 3.24-3. 49 (m, 3H, C3H ' , C5H and C8H), 2.12-2.26 (m, 1H , C6H or _{C7H), 2.09 (s, 3H} , CH 3), 2.08 (s, 3H _{, CH 3), 1.83-1.95 (m} , 2H, C6H2 or _{C7H2), 1.78 (s, 3H} , CH 3), 1.62 (s, 3H, CH 3), 1.50- 1.60 (m, 1H, C6H or C7H), 1.50 (s, 9H , C (CH 3 _{3), 1.38 (s, 9H} , C (CH 3) 3); 13 C NMR (75.5 MHz, C 6 D 6) δ C = 146.73,146.68,146.05,146. 03, 144.59, 44.40, 138.52, 138.50, 138.48, 138.45, 137.30, 135.32, 134.59, 132.66, 132.24, 132.19, 131.62, 131.27, 131.24 (ArCquat.), 128.71, 128.69, 128.62, 128.34, 128.25, 128.00, 127.96, 126.14, 126. 12, 126.04, 126.02 (ArCH), 62.40 (dd, 1JC-P = 29.0, 3.7 Hz, C3), 46.20 (d, 1JC-P = 15.9 Hz, C5 also Is C8), 45.45 (d, 1JC-P = 14.9 Hz, C5 or C8), 36.42 (C6 or C7), 32.67 (d, 2JC-P = 3.1 Hz, C6 or C7), 31.76 (d, J = 5.0 Hz, C (CH ₃ ) ₃ ), 31.29 (C (CH ₃ ) ₃ ), 20.4 (CH ₃ ), 20.37 (CH ₃ ), 16.74 (CH ₃ ), 16.45 (CH ₃ ).

(Example 2)
Regioselective and enantioselective hydroformylation of allylbenzene. [Rh (acac) (CO) ₂ ] (1 mg, 0.004 mmol, 0.4 mol%) is added into the vial, a stir bar is added, the vial is sealed with a crimp cap and under an inert atmosphere (N ₂ ). Put it on. Two needles were inserted into the vial and introduced into the autoclave. The autoclave was then purged with 3 vacuum / N ₂ cycles. A solution of ligand (Ligand 3a, 3.3 mg, 0.005 mmol, 0.5 mol%) from the stock solution in toluene (1 mL) was added using a syringe. The autoclave was then purged 3 times with synthesis gas (50/50, CO / H ₂ ), pressurized to 5 bar and immersed in an oil bath preheated to 50 ° C., 900 r. p. m for 40 minutes. The autoclave was then cooled to room temperature by partially immersing it in cold water and the pressure was released. A solution of alkene (allylbenzene, 118 mg, 133 μl, 1 mmol) and internal standard (tetraethylsilane, 30 μl) in toluene (1 mL) was added using a syringe. The autoclave is then pressurized back to the desired pressure (5 bar) and at room temperature, 900 r. p. m. Stir with. After the desired reaction time (75 hours), the pressure was gradually released and the autoclave was opened. A small sample was taken and analyzed by ¹ H NMR (CDCl ₃ ) to calculate the conversion (64%) and the branched to linear ratio (4.00: 1) of the resulting aldehyde. . To determine enantioselectivity (ee = 90% for branched aldehydes), the product was converted to the corresponding alcohol by NaBH ₄ reduction and the alcohol product was worked up (dichloromethane (5 mL), HCl. Quenched with aqueous solution (5 mL, 1M), then obtained after 3 further extractions with dichloromethane (3 × 10 mL)). The combined organic layers are dried over anhydrous MgSO ₄ and the solvent is removed using a rotary evaporator to give a crude mixture, which is purified by chromatography using hexane / EtOAc 4: 1 as the eluent. This gave branched and linear alcohols as colorless oil (79 mg, 53%). [Α] _D ^rt = −12.2 (c 0.5, CHCl ₃ ) (for branched alcohol).

  NMR data for branched and straight chain alcohols.

２−メチル−３−フェニルプロパン−１−オール：^１Ｈ ＮＭＲ （３００ ＭＨｚ，ＣＤＣｌ_３）： δ＝ ０．９０ （３Ｈ，ｄ，Ｊ＝６．８ Ｈｚ），１．４３ （１Ｈ，ｂｒ ｓ），１．８７−１．９９ （１Ｈ，ｍ），２．４１ （１Ｈ，ｄｄ，Ｊ＝１３．４，８．１ Ｈｚ），２．７４ （１Ｈ，ｄｄ，Ｊ＝１３．４，６．３ Ｈｚ），３．４６ （１Ｈ，ｄｄ，Ｊ＝１０．６，６．０ Ｈｚ），３．５２ （１Ｈ，ｄｄ，Ｊ＝１０．６，５．９ Ｈｚ），７．１４−７．２８ （５Ｈ，ｍ）； ＭＳ（ＥＳ＋）：１７３．１（［ＭＮａ］^＋、１００％）。

2-Methyl-3-phenylpropan-1-ol: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.90 (3H, d, J = 6.8 Hz), 1.43 (1H, br s ), 1.87-1.99 (1H, m), 2.41 (1H, dd, J = 13.4, 8.1 Hz), 2.74 (1H, dd, J = 13.4, 6) .3 Hz), 3.46 (1H, dd, J = 10.6, 6.0 Hz), 3.52 (1H, dd, J = 10.6, 5.9 Hz), 7.14-7 .28 (5H, m); MS (ES +): 173.1 ([MNa] ⁺ , 100%).

4-Phenylbutan-1-ol: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 1.38 (1H, br s), 1.55-1.72 (4H, m), 2.62 (2H , T, J = 7.5 Hz), 3.64 (2H, t, J = 6.4 Hz), 7.15-7.28 (5H, m); MS (ES +): 173.1 ([ MNa] ⁺ , 100%). The enantiomeric excess of the branched alcohol was determined using a Chiralcel ™ OD-H column, 250 × 4.6 mm, 95: 5 n-hexane: 2-propanol, 0.5 ml / min, 210 nm, t _R [(− )-(S), major] = 18.6 min, t _R [(+)-(R), minor] = 22.8 min, t _R [linear] = 30.2 Judged by HPLC in minutes.

(Example 3)
Regioselective and enantioselective hydroformylation of hexa-1-ene. [Rh (acac) (CO) ₂ ] (1 mg, 0.004 mmol, 0.4 mol%) is added into the vial, a stir bar is added, the vial is sealed with a crimp cap and under an inert atmosphere (N ₂ ). Put it on. Two needles were inserted into the vial and introduced into the autoclave. The autoclave was then purged with 3 vacuum / N ₂ cycles. A toluene (1 ml) solution of the ligand from the stock solution (ligand 3a, 3.3 mg, 0.005 mmol, 0.5 mol%) was added using a syringe. The autoclave was then purged 3 times with synthesis gas (50/50, CO / H ₂ ), pressurized to 5 bar and immersed in an oil bath preheated to 50 ° C., 900 r. p. m for 40 minutes. The autoclave was then cooled to room temperature by partially immersing it in cold water and the pressure was released. A solution of alkene (1-hexene, 84 mg, 124 μl, 1 mmol) and internal standard (tetraethylsilane, 30 μl) in toluene (1 ml) was added using a syringe. The autoclave is then pressurized back to the desired pressure (5 bar) and at room temperature, 900 r. p. m. Stir with. After the desired reaction time (46 hours), the pressure was gradually released and the autoclave was opened. A small sample was taken and analyzed by ¹ H NMR (CDCl ₃ ) to calculate the conversion (70%) and the branched to linear ratio (2.98: 1) of the resulting aldehyde. . To determine enantioselectivity (ee = 93% for branched aldehydes) by reducing the product using NaBH ₄ and protection by standard methods to the Cbz-ester of the corresponding alcohol. Converted. NMR data for branched and straight chain alcohols. [Α] _D ²⁰ -11.6 (c 1.4, CHCl ₃ ee 93%)

２−メチルヘキサン−１−オール：^１Ｈ ＮＭＲ （３００ ＭＨｚ，ＣＤＣｌ_３）： δ＝ ０．８９ （３Ｈ，ｔ，Ｊ＝６．９ Ｈｚ），０．９１ （３Ｈ，ｄ，Ｊ＝６．７ Ｈｚ），１．０５−１．６７ （８Ｈ，ｍ），３．４０ （１Ｈ，ｄｄ，Ｊ＝１０．５，６．５ Ｈｚ），３．５０ （１Ｈ，ｄｄ，Ｊ＝１０．５，５．８ Ｈｚ）； ＭＳ（ＥＳ＋）：１３９．１（［ＭＮａ］^＋、１００％）。

2-Methylhexane-1-ol: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.89 (3H, t, J = 6.9 Hz), 0.91 (3H, d, J = 6. 7 Hz), 1.05-1.67 (8 H, m), 3.40 (1 H, dd, J = 10.5, 6.5 Hz), 3.50 (1 H, dd, J = 10.5) , 5.8 Hz); MS (ES +): 139.1 ([MNa] ⁺ , 100%).

Heptan-1-ol: ¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.88 (3H, t, J = 6.4 Hz), 1.28-1.60 (11H, m), 3. 63 (2H, t, J = 6.6 Hz); MS (ES +): 139.1 ([MNa] ⁺ , 100%). The enantiomeric excess of branched Cbz-derived alcohol was determined as Chiralpak ™ AD-H, 250 × 4.6 mm and Chiralcel ™ OD-H, 250 × 4.6 mm tandem, 99: 1 n-hexane: 2 -Propanol, 0.5 ml / min, 210 nm, t _R [(-)-(S), major] = 20.5 min, t _R [(+)-(R), minor] = 25.2 min, t _R [Linear] determined by HPLC at 24.2 minutes.

Example 4
Regioselective and enantioselective hydroformylation of pentafluoro-allylbenzene. A branched aldehyde was again formed using the same procedure as described in Examples 2 and 3, but using pentafluoro-allylbenzene as substrate and a reaction temperature of 40 ° C. After the desired reaction time (4 hours), the pressure was gradually released and the autoclave was opened. A small sample was taken and analyzed by ¹ H NMR (CDCl ₃ ) to calculate the conversion (90%) and the branched to linear ratio (5.3: 1) of the resulting aldehyde. . To determine enantioselectivity (ee = 88% for branched aldehydes), the aldehyde was reduced using NaBH ₄ in a standard manner and hexane / EtOAc 4: 1 was used as the eluent. Standard purification by chromatography on silica gel gave branched and linear alcohols as colorless oil (150 mg, 63%). _{^{[Α] D 20 = -8.7 (}} . C 2.75, CHCl 3, e.e 88%);

（−）−２−メチル−３−（ペルフルオロフェニル）プロパン−１−オール。^１Ｈ ＮＭＲ （４００ ＭＨｚ，ＣＤＣｌ_３）： δ_Ｈ＝０．９２ （ｄ，Ｊ＝６．８ Ｈｚ，３Ｈ），１．７７ （ｓ，１Ｈ），１．８９−２．０１ （ｍ，１Ｈ），２．５５ （ｄｄｔ，Ｊ＝１３．６，８．４，１．７ Ｈｚ，１Ｈ），２．８５ （ｄｄｔ，Ｊ＝１３．６，５．８，１．７ Ｈｚ，１Ｈ），３．５０ （ｄｄ，Ｊ＝８．９，４．２ Ｈｚ，１Ｈ），３．５４ （ｄｄ，Ｊ＝８．９，４．０ Ｈｚ，１Ｈ）； ^１９Ｆ ＮＭＲ （３７６ ＭＨｚ，ＣＤＣｌ_３）： δ_Ｆ＝−１６３．６− −１６３．４ （ｍ，２Ｆ），−１５８．２ （ｔ，Ｊ＝２０．８ Ｈｚ，１Ｆ），−１４３．７− −１４３．６ （ｍ，２Ｆ）； ^１３Ｃ ＮＭＲ （７５ ＭＨｚ，ＣＤＣｌ_３）： δ_Ｃ＝１６．０，２５．９，３６．２，６７．３，１１３．７−１１４．０ （ｍ），１３６．１−１４６．４ ８ （ｍ）； ＭＳ（Ｃｌ^＋）：２３９．０（［Ｍ−２Ｈ＋Ｈ］^＋、１００％）、２４０（［ＭＨ］^＋、１３）、２５０．０（［Ｍ＋ＮＨ_４］^＋、８）；ＨＲＭＳ（Ｃｌ＋）：ｍ／ｚ＝２５８．０９１４［Ｍ＋ＮＨ_４］^＋、Ｃ_１０Ｈ_１３ＯＮＦ_５は、２５８．０９１２を必要とする。

(−)-2-Methyl-3- (perfluorophenyl) propan-1-ol. ¹ H NMR (400 MHz, CDCl ₃ ): δ _H = 0.92 (d, J = 6.8 Hz, 3H), 1.77 (s, 1H), 1.89-2.01 (m, 1H ), 2.55 (ddt, J = 13.6, 8.4, 1.7 Hz, 1H), 2.85 (ddt, J = 13.6, 5.8, 1.7 Hz, 1H), 3.50 (dd, J = 8.9, 4.2 Hz, 1H), 3.54 (dd, J = 8.9, 4.0 Hz, 1H); ¹⁹ F NMR (376 MHz, CDCl ₃ ) : Δ _F = −163.6−−163.4 (m, 2F), −158.2 (t, J = 20.8 Hz, 1F), −143.7−−143.6 (m, 2F) ^{; 13 C NMR (75 MHz,} CDCl 3): δ C = 16.0,25.9,36.2,67.3,113.7-114.0 ( ^{), 136.1-146.4 8 (m);} MS (Cl +): 239.0 ([M-2H + H] +, 100%), 240 ([MH] +, 13), 250.0 ([ M + NH ₄ ] ⁺ , 8); HRMS (Cl +): m / z = 258.0914 [M + NH ₄ ] ⁺ , C ₁₀ H ₁₃ ONF ₅ requires 258.0912.

4- (Perfluorophenyl) butan-1-ol. ¹ H NMR (400 MHz, CDCl ₃ ): δ _H = 1.46 (br s, 1H), 1.57-1.72 (m, 4H), 2.72-2.75 (m, 2H), 3.67 (t, J = 6.2 Hz, 2H); ¹⁹ F NMR (376 MHz, CDCl ₃ ): δ _F = −163.5−−163.4 (m, 2F), −158.5 ( t, J = 20.9 Hz, 1F), -144.9--144.8 (m, 2F); ¹³ C NMR (100 MHz, CDCl ₃ ): δ _C = 22.0, 25.5, 32 0.0, 62.3, 114.7-115.0 (m), 136.1-146.3 (m). Enantiomeric excess of branched alcohol was determined using Chiralpak ™ AS-H column, 250 × 4.6 mm and Chiralpak AD-H column, 250 × 4.6 mm tandem series, 99: 1 n-hexane: 2- Propanol, 0.5 mL / min, 210 nm, t _R [(−), major] = 69.1 min, t _R [(+), minor] = 74.0 min, t _R [linear] = 97. Judged by HPLC at 2 minutes.

(Example 5)
Regioselective and enantioselective hydroformylation of N-methyl-N-phenylbut-3-enamide. A similar procedure as described in Examples 2 and 3, but again using the N-methyl-N-phenylbut-3-enamide as substrate and a reaction temperature of 15 ° C., the branched aldehyde was re-formed. . After the desired reaction time (29 hours), the pressure was gradually released and the autoclave was opened. A small sample was taken and analyzed by ¹ H NMR (CDCl ₃ ) to calculate the conversion (71%) and the branched to linear ratio (4.5: 1) of the resulting aldehyde. . In order to determine enantioselectivity (ee = 92% for branched aldehydes), the aldehyde was reduced using NaBH ₄ in a standard way and using SiO ₂ as the eluent on SiO ₂ . Standard purification by chromatography gave branched and linear alcohols as colorless oil (113 mg, 55%). _{^{[Α] D 20 -7.7 (.}} C 0.85, CHCl 3, e.e 92%);

（−）−４−ヒドロキシ−Ｎ，３−ジメチル−Ｎ−フェニルブタンアミド。溶離液としてＥｔＯＡｃを使用してシリカゲルでのクロマトグラフィーによって精製することによって、無色油状物として分岐状および直鎖状アルコールを得た（１１３ｍｇ、５５％）。［α］_Ｄ ^２０ −７．７（ｃ ０．８５、ＣＨＣｌ_３、ｅ．ｅ． ９２％）；^１Ｈ ＮＭＲ （３００ ＭＨｚ，ＣＤＣｌ_３）： δ＝０．７９ （ｄ，Ｊ＝６．３ Ｈｚ，３Ｈ），２．００−２．２１ （ｍ，３Ｈ），３．２４ （ｓ，３Ｈ），３．２９−３．３４ （ｍ，２Ｈ），３．５０ （ｄｄ，Ｊ＝１０．３，３．４ Ｈｚ，１Ｈ），７．１４−７．１８ （ｍ，２Ｈ），７．３０−７．４３ （ｍ，３Ｈ）； ^１３Ｃ ＮＭＲ （７５ ＭＨｚ，ＣＤＣｌ_３）： δ＝１７．２，３３．１，３７．４，３８．９，６８．１，１２７．２，１２７．８，１２９．８，１４３．９，１７３．２； ＭＳ（ＥＳ^＋）：２３０．０（［ＭＮａ］^＋、１００％）；ＨＲＭＳ（ＥＳ^＋）：ｍ／ｚ＝２３０．１１６１［ＭＮａ］^＋、Ｃ_１２Ｈ_１７ＮＯ_２Ｎａは、２３０．１１５７を必要とする。

(−)-4-Hydroxy-N, 3-dimethyl-N-phenylbutanamide. Purification by chromatography on silica gel using EtOAc as the eluent gave the branched and linear alcohols as a colorless oil (113 mg, 55%). [Α] _D ²⁰ −7.7 (c 0.85, CHCl ₃ , ee 92%); ¹ H NMR (300 MHz, CDCl ₃ ): δ = 0.79 (d, J = 6.3) Hz, 3H), 2.00-2.21 (m, 3H), 3.24 (s, 3H), 3.29-3.34 (m, 2H), 3.50 (dd, J = 10. 3, 3.4 Hz, 1H), 7.14-7.18 (m, 2H), 7.30-7.43 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ = 17 2, 33.1, 37.4, 38.9, 68.1, 127.2, 127.8, 129.8, 143.9, 173.2; MS (ES ⁺ ): 230.0 ([ ^{MNa] +, 100%);} HRMS (ES +): m / z = 230.1161 [MNa] +, C 12 H 17 NO 2 Na is It requires 230.1157.

5-Hydroxy-N-methyl-N-phenylpentanamide. ¹ H NMR (300 MHz, CDCl ₃ ): δ _H = 1.42-1.51 (m, 2H), 1.61-1.70 (m, 2H), 2.09 (t, J = 7. 0 Hz, 2H), 2.24 (br s, 1H), 3.25 (s, 3H), 3.54 (t, J = 6.3 Hz, 2H), 7.15-7.18 (m , 2H), 7.31-7.44 (m, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ _C = 21.2, 32.2, 33.6, 37.4, 62.0 , 127.3, 127.9, 129.8, 144.1, 173.3; MS (ES ⁺ ): 230.0 ([MNa] ⁺ , 100%). The enantiomeric excess of branched alcohol was determined using a Chiralpak ™ AD-H column, 250 × 4.6 mm, 93: 7 n-hexane: 2-propanol, 0.5 mL / min, 254 nm, t _R [(− ), Major] = 33.8 minutes, t _R [(+), minor] = 36.2 minutes, t _R [linear] = 41.2 minutes.

(Example 6)
Regioselective and enantioselective hydroformylation of vinyl acetate. This reaction was performed in an Argonaut Endeavor parallel autoclave system (AE). The AE vessel was flushed with synthesis gas. A stock solution of [Rh (acac) (CO) ₂ ] and ligand 3a was prepared as a 1 mg toluene solution per mL. 1 ml of rhodium stock solution (1 mg, 0.004 mmol, 0.4 mol%) and 0.005 mmol (0.5%) of stock solution equivalent to ligand 3a were added to the wells in AE. The mixture was pressurized with 5 bar synthesis gas and heated at 50 ° C. for 40 minutes. The pressure was then released and the apparatus was cooled to room temperature. The required substrate (1 mmol vinyl acetate) was then added, again as a stock solution in toluene, to bring the reactor up to a volume of 3.5 mL. The apparatus was then purged 3 times with synthesis gas, placed at a pressure of 2.5 bar and heated to 60 ° C. for 4 hours at a constant pressure. Thereafter, no further syngas was used (over 99% conversion). The AE was then cooled and the reaction mixture was analyzed by GC using a β-Dex225 chiral column with a standard protocol. This is because with NMR, only the products present are branched aldehydes (B / L> 99: 1), e. e. Was found to be 83%.

(Example 7)
Regioselective and enantioselective hydroformylation of styrene. This reaction was performed in an Argonaut Endeavor parallel autoclave system (AE). The AE vessel was flushed with synthesis gas. A stock solution of [Rh (acac) (CO) ₂ ] and ligand 3a was prepared as a 1 mg toluene solution per mL. 1 ml of rhodium stock solution (1 mg, 0.004 mmol, 0.4 mol%) and 0.005 mmol (0.5%) of stock solution equivalent to ligand 3a were added to the wells in AE. The mixture was pressurized with 5 bar synthesis gas and heated at 50 ° C. for 40 minutes. The pressure was then released and the apparatus was cooled to room temperature. The required substrate (styrene, 1 mmol) was then added, also as a stock solution in toluene, to bring the reactor up to a volume of 3.5 mL. The apparatus was then purged 3 times with synthesis gas, placed at a pressure of 10 bar and heated to 60 ° C. for 16 hours at a constant pressure. Thereafter, no further syngas was used (over 99% conversion). The AE was then cooled and the reaction mixture was analyzed by GC using a β-Dex225 chiral column with a standard protocol. This is greater than 99% conversion to aldehyde (B / L = 79.3: 1), and e. e. Was 92%.

(Example 8)
Regioselective and enantioselective hydroformylation of allyl cyanide. This reaction was performed in an Argonaut Endeavor parallel autoclave system (AE). The AE vessel was flushed with synthesis gas. A stock solution of [Rh (acac) (CO) ₂ ] and ligand 3a was prepared as a 1 mg toluene solution per mL. 1 ml of rhodium stock solution (1 mg, 0.004 mmol, 0.4 mol%) and 0.005 mmol (0.5%) of stock solution equivalent to ligand 3a were added to the wells in AE. The mixture was pressurized with 5 bar synthesis gas and heated at 50 ° C. for 40 minutes. The pressure was then released and the apparatus was cooled to room temperature. The required substrate (allyl cyanide, 1 mmol) was then added, again as a stock solution in toluene, to bring the reactor up to a volume of 3.5 mL. The apparatus was then purged 3 times with synthesis gas, placed at a pressure of 10 bar and heated to 30 ° C. for 14 hours at a constant pressure. Thereafter, no further syngas was used (over 99% conversion). The enantiomeric excess is then calculated by cooling the AE and analyzing the reaction mixture by ¹ H NMR spectroscopy utilizing enantiopure (R) -1-phenylpropan-1-amine as the chiral derivatizing agent. Promoted and branched selectivity and conversion were also measured using NMR. In some cases, conversion, branched versus linear, was also confirmed using chiral CG using an α-Dex225 column. This is greater than 99% conversion, B: L = 10.0: 1, and 81% e.e. e. Was revealed.

  Throughout this application, various publications are referenced. The entire disclosures of these publications are hereby incorporated by reference into this application in order to more fully describe the state of the art known to those skilled in the art at the date of the invention described and claimed herein. ing.

  While particular embodiments of the present invention have been illustrated and described, it should be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. Accordingly, it is intended to embrace all such changes and modifications as fall within the scope of the appended claims.

Claims (17)

Compound of formula 4:

Wherein n and m are each independently an integer of 1 to 3;
Both Ar ¹ are independently C ₆ -C ₁₄ aryl or C ₁ -C ₉ heteroaryl, which, if unsubstituted, are the following groups: C ₁ -C ₆ alkyl-, halogen, C ₁ -C ₆ haloalkyl -, hydroxyl, hydroxyl _(C 1 -C _{6 alkyl) -, H 2 N -,} (C 1 ~C 6 alkyl) amino -, di _(C 1 -C ₆ alkyl) amino -, HO ₂ C-, (C ₁ -C ₆ alkoxy) carbonyl-, (C ₁ -C ₆ alkyl) carboxyl-, di (C ₁ -C ₆ alkyl) amide-, H ₂ NC (O)-, (C _1- C ₆ alkyl) amido-, or optionally substituted with one or more of O ₂ N-
—Ar ² —Ar ² — is bi (C ₆ -C ₁₄ aryl), bi (C ₁ -C ₉ heteroaryl), or — (C ₆ -C ₁₄ aryl)-(C ₁ -C ₉ heteroaryl). A diradical, which is unsubstituted, even if unsubstituted, the following groups: C ₁ -C ₆ alkyl-, halogen, C ₁ -C ₆ haloalkyl-, hydroxyl, hydroxyl (C ₁ -C ₆ alkyl)- _{, H 2 N -, (C} 1 ~C 6 alkyl) amino -, di _(C 1 -C ₆ alkyl) amino _{-, HO 2 C -, (} C 1 ~C 6 alkoxy) carbonyl _{-, (C} 1 -C ₆ alkyl) carboxyl-, di (C ₁ -C ₆ alkyl) amide-, H ₂ NC (O)-, (C ₁ -C ₆ alkyl) amide-, or O ₂ N- May be substituted). —Ar ² —Ar ² — is a bi (C ₆ -C ₁₄ aryl) diradical, which, even if unsubstituted, has the following groups: C ₁ -C ₆ alkyl-, halogen, C _1- C ₆ haloalkyl-, hydroxyl, hydroxyl (C ₁ -C ₆ alkyl)-, H ₂ N—, (C ₁ -C ₆ alkyl) amino-, di (C ₁ -C ₆ alkyl) amino-, HO ₂ C— , (C ₁ -C ₆ alkoxy) carbonyl-, (C ₁ -C ₆ alkyl) carboxyl-, di (C ₁ -C ₆ alkyl) amide-, H ₂ NC (O)-, (C ₁ -C ₆ alkyl) _2. The compound of claim 1, optionally substituted with one or more of amide-, or O2N-. —Ar ² —Ar ² — is a biphenyl diradical, which, even if unsubstituted, has the following groups: C ₁ -C ₆ alkyl-, halogen, C ₁ -C ₆ haloalkyl-, hydroxyl, hydroxyl _(C 1 -C _{6 alkyl) -, H 2 N -,} (C 1 ~C 6 alkyl) amino -, di _(C 1 -C ₆ alkyl) amino _{-, HO 2 C -, (} C 1 ~C 6 alkoxy ) Carbonyl-, (C ₁ -C ₆ alkyl) carboxyl-, di (C ₁ -C ₆ alkyl) amide-, H ₂ NC (O) —, (C ₁ -C ₆ alkyl) amide-, or O ₂ N 3. The compound of claim 2, which is optionally substituted with one or more of-. —Ar ² —Ar ² — is a 2,2′-biphenyl diradical, which, even if unsubstituted, has the following groups: C ₁ -C ₆ alkyl-, halogen, C ₁ -C ₆ haloalkyl-, hydroxyl, hydroxyl _(C 1 -C _{6 alkyl) -, H 2 N -,} (C 1 ~C 6 alkyl) amino -, di _(C 1 -C ₆ alkyl) amino _{-, HO 2 C -, (} C 1 ~ C ₆ alkoxy) carbonyl-, (C ₁ -C ₆ alkyl) carboxyl-, di (C ₁ -C ₆ alkyl) amide-, H ₂ NC (O)-, (C ₁ -C ₆ alkyl) amide-, or O 2 _N-may be substituted by one or more of the compound according to claim 3. -Ar ² -Ar ² - is one or more _C 1 -C ₆ 2,2'-biphenyl diradical substituted with an alkyl group, The compound of claim 4. Ar ¹ are both a _C 6 _{-C 14} aryl, independently, a compound according to any one of claims 1 to 5. The compound according to any one of claims 1 to 6, wherein Ar ¹ is both phenyl.   The compound according to any one of claims 1 to 7, wherein n and m are both 1. 9. A compound according to any one of claims 1 to 8 having the formula 1, 2a, 2b, 3a or 3b:

10. The compound of claim 9, having formula 3b:

A process for synthesizing a ligand of formula 4 according to claim 1, wherein the process comprises:

Wherein X is a leaving group.   A process for the asymmetric hydroformylation of a prochiral olefin in the presence of an Rh catalyst obtained from a ligand of formula 4 according to claim 1. Said prochiral terminal olefin is _{RCH 2} CH = CH 2, wherein, _{R, C} 6 -C _aryl, C 1 -C ₉ heteroaryl, or _C 1 -C ₆ alkyl, any _C 6 -C Aryl, C ₁ -C ₉ heteroaryl, or C ₁ -C ₆ alkyl group can be any of the following groups: halogen, H ₂ N—, (C ₁ -C ₆ alkyl) amino-, di (C ₁ -C ₆ alkyl) ) Amino-, (C ₁ -C ₆ alkyl) C (O) N (C ₁ -C ₃ alkyl)-, (C ₁ -C ₆ alkyl) carboxamide-, HC (O) NH—, H ₂ NC ( _{O) -, (C 1 ~C} 6 alkyl) NHC (O) -, di _(C 1 -C ₆ alkyl) NC (O) -, NC- , _hydroxyl, C 1 -C ₆ alkoxy _-, C 1 -C ₆ alkyl _{-, HO 2 C -, (} C 1 ~C 6 Al Kokishi) carbonyl _{-, (C} 1 ~C _{6 alkyl) C (O) -, C} 6 ~C 14 aryl _-, C 1 ~C ₉ heteroaryl _-, C 3 ~C ₈ cycloalkyl _-, C 1 ~C ₆ Optionally by one or more of haloalkyl-, amino (C ₁ -C ₆ alkyl)-, (C ₁ -C ₆ alkyl) carboxyl-, C ₁ -C ₆ carboxyamidoalkyl-, or O ₂ N-. The process according to claim 12, wherein the process is substituted. 13. The process according to claim 12, wherein the prochiral olefin is styrene and the hydroformylation uses synthesis gas in the presence of an Rh catalyst obtained from a ligand of formula 4,

Including the process. 13. A process according to claim 12, wherein the prochiral olefin is allyl cyanide and the hydroformylation uses synthesis gas in the presence of an Rh catalyst obtained from a ligand of formula 4, Is

Including the process. 13. The process according to claim 12, wherein the prochiral olefin is vinyl acetate and hydroformylation uses synthesis gas in the presence of an Rh catalyst obtained from a ligand of formula 4,

Including the process.   14. The process of claim 13, wherein the regioselectivity of hydroformylation supporting a linear aldehyde product is reversed to a branched aldehyde product.